Intracellular Levels of Two Cyclosporin Derivatives Valspodar (PSC 833) and Cyclosporin A Closely Associated with Multidrug Resistance‐modulating Activity in Sublines of Human Colorectal Adenocarcinoma HCT‐15

• Published in: Cancer science Vol. 92; no. 10; pp. 1116 - 1126
• Main Authors: Uchiyama‐Kokubu, Noriko, Watanabe, Toru, Cohen, Dalia
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-10-2001; Japanese Cancer Association; John Wiley & Sons, Inc
• Subjects: Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Anticarcinogenic Agents - pharmacology; Antineoplastic agents; Antineoplastic drugs; Antitumor agents; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Benzoic acid; Biological and medical sciences; Biological Transport - drug effects; Cell Division - drug effects; Chemotherapy; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Cyclosporin A; Cyclosporine - metabolism; Cyclosporine - pharmacology; Cyclosporine - therapeutic use; Cyclosporins - metabolism; Cyclosporins - pharmacology; Cyclosporins - therapeutic use; Doxorubicin - pharmacology; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Flow Cytometry; General aspects; Glycoproteins; Humans; Inhibitory Concentration 50; Intracellular; Intracellular Fluid - drug effects; Intracellular Fluid - metabolism; Intracellular levels; Medical sciences; Multidrug resistance; Multidrug resistance‐Correlation; Paclitaxel; Pharmacology. Drug treatments; P‐Glycoprotein; Rhodamine; Rhodamine 123 - metabolism; Tumor Cells, Cultured; Valspodar; Verapamil; Verapamil - pharmacology; Vincristine; Adenocarcinoma; Antineoplastic agent; P Glycoprotein; Doxorubicin; Alkaloid; Isomerases; Multiple resistance; Taxane derivatives; Established cell line; Paclitaxel; Intestinal disease; Ciclosporin; Colon; Antimitotic; Human; DNA topoisomerase (ATP-hydrolysing); Treatment resistance; Enzyme; Enzyme inhibitor; Malignant tumor; In vitro; Cell subpopulation; Vincristine; Valspodar; Colonic disease; Analog; Rectum; Digestive diseases; Reversibility; Anthracyclins; Intracellular
• ISSN: 0910-5050; 1347-9032; 1349-7006; 1876-4673
• DOI: 10.1111/j.1349-7006.2001.tb01067.x

P‐Glycoprotein, which mediates multidrug resistance (MDR) in cancer chemotherapy, is a principal target of Cyclosporin A and [3′‐keto‐Bmt1]‐[Val2]‐cyclosporin (valspodar; PSC 833). To clarify mechanisms contributing to the different MDR‐modulating activities of valspodar and Cyclosporin A, we investigated the relation of the intracellular levels of the two Cyclosporin derivatives to their modulating effect on MDR in different P‐glycoprotein‐expressing human colorectal carcinoma HCT‐15 cells (parental HCT‐15 and adriamycin‐resistant sublines). In this study, valspodar was found to be much more potent than Cyclosporin A in both sensitizing resistant cells to MDR‐related anticancer drugs (e.g., adriamycin, vincristine and paclitaxel (taxol)) and increasing 2‐[6‐amino‐3‐imino‐3H‐xanthen‐9‐yl]benzoic acid methyl ester (rhodamine 123) retention and [G‐3H]vincristine sulfate ([3H]vincristine) accumulation in these cells. Furthermore, a good correlation was detected between P‐glycoprotein levels and the MDR‐reversing effect of valspodar. In contrast, the effects of Cyclosporin A could not be linked to P‐glycoprotein levels in the MDR cells. In addition, the intracellular accumulation of valspodar was found to be 3–6 fold higher than that of Cyclosporin A in four sublines and verapamil, an inhibitor of P‐glycoprotein‐mediated transport, enhanced the accumulation of Cyclosporin A, but not valspodar. These results suggested that valspodar accumulation is not actively regulated by the P‐glycoprotein‐mediated efflux system